Cannabinoid receptors (CBRs) belong to the endocannabinoid (EC) system, which consists of receptors, transporters, endocannabinoids, and enzymes involved in synthesis and degradation of endocannabinoids. The EC system regulates many important physiological processes and several components of the EC system are under evaluation as targets to treat a diverse array of indications including obesity, liver disease, diabetes, pain and inflammation. To date, two different cannabinoid receptors have been identified (referred to as CB1 and CB2). CB1 and CB2 receptors fall within the class of G protein-coupled receptors, and primarily function to activate inhibitory G proteins (Gi/o).
The CB1 receptor is prominently expressed in the central nervous system (CNS) and also in peripheral tissues. Accordingly, drugs tarteting the CB1 receptors have been developed over the years to treat various metabolic disorders including obesity and diabetes. The first drug selective for CB1 that was developed for medical use was rimonabant, an inverse agonist/antagonist. Rimonabant was designed to treat obesity and other related disorders that have both CNS and peripheral components. Although rimonabant has demonstrated clinical efficacy in clinical trials, it was withdrawn from European markets and denied FDA approval in the United States due to CNS-related side effects including anxiety, depression and suicidal ideation. The development of other related compounds (e.g., taranabant, otenabant, and ibipinabant) was discontinued based on these noted side effects. Accordingly, it would be beneficial to provide CB1 antagonists that are effective, but that do not result in such CNS-related side effects.